Community-associated (CA) skin and soft tissue infections (SSTIs) pose a substantial health burden worldwide. SSTI incidence in the U.S. has increased 50% in the past decade resulting in over 10 million visits to healthcare providers annually. This increase is driven by the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains, which now cause the majority of SSTIs. No other infectious disease has seen such a dramatic rise. Of great concern is that SSTIs are complicated by high rates of recurrence (>50% in 1 year), as well as hospitalization, severe sepsis, and even death. Current guidelines inadequately address the role of older, inexpensive antibiotics for SSTI treatment. The disconnect between the high incidence of SSTIs, which exceed that of pneumonia and urinary tract infections, and the lack of data to guide prescribing physicians is unjustifiable and can only be addressed by high quality clinical trials. Recent studies have demonstrated that clindamycin and trimethoprim- sulfamethoxazole (TMP-SMX) have similar efficacy and safety for uncomplicated SSTIs (uSSTIs). Both have efficacy, when combined with incision and drainage, that exceeds that of placebo. However, clindamycin resistance among S. aureus in the U.S. is increasing and exceeds 90% in some parts of the world. TMP-SMX is also limited by higher rates of recurrent SSTIs compared to clindamycin and by emergence of TMP-SMX resistance among S. aureus in populations where use of TMP-SMX is high. Doxycycline is the natural choice for study of uSSTI treatment. Its tolerability, low cost, and promising preliminary data for SSTI management suggest it is efficacious and safe for uSSTI treatment. Unfortunately, high quality comparative effectiveness data for SSTI treatment with doxycycline are lacking. We will perform a clinical trial of uSSTIs, targeting infections likely to be caused by CA-MRSA and populations previously ignored in other trials of SSTIs (e.g., diabetics, obese persons). We will compare the efficacy and safety of doxycycline versus TMP-SMX for the treatment of suppurative uSSTI in older children and adults. We will also compare efficacy of preventing recurrent uSSTIs up to 12 months after initial treatment and define the relationship between nasal and oropharyngeal colonization and treatment success and recurrence. We will quantify and characterize emergent colonizing antibiotic-resistant S. aureus isolates. Finally, we will develop a new clinical trial outcome for SSTIs using the Desirability Of Outcome Ranking (DOOR) design for this trial. This outcome will complement our more traditional primary outcome by capturing meaningful patient-centered outcomes. DOOR outcomes can reduce sample size of future SSTI clinical trials, thus making future trials less expensive and more feasible. Our investigation will be critical in defining the role of doxycycline for uSSTI treatment and lay the foundation for evidence-based therapies that improve short and long term patient outcomes in this extremely common yet understudied infection.